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For instance, if "Biomarkers" and "Genetics" are selected in the Topic category, and "Multiple sclerosis" is selected in the Disease category, all results that match EITHER the Biomarkers OR Genetics Topic category will be shown, but only if they also match the Multiple sclerosis Disease category; i.e. Boolean search of [("Biomarkers" OR "Genetics") AND "multiple sclerosis"]

ALS, PARP Diem?

James Shorter thinks it just might. In three recent papers, researchers in Shorter’s group and that of Nancy Bonini, both at the University of Pennsylvania in Philadelphia, reported that inhibitors of poly(ADP-ribose) polymerases (PARPs) keep the ALS-linked protein TDP-43 in the nucleus where it belongs, and protect neurons from its toxic effects (McGurk et al., 2018;McGurk et al., 2018). Moreover, their work helps explain why cytoplasmic TDP-43 forms aggregates (McGurk et al., 2018).

A spoonful less of sugar? Inhibiting tankyrase may help protect neurons in ALS by reducing the accumulation of TDP-43 in cytoplasmic aggregates, enabling the RNA regulator to return to the nucleus. [Courtesy of McGurk et al., 2018, Molecular Cell.]

PARPs are a family of enzymes that add PAR groups to other proteins. There are 17 known PARPs in mammals, and they have many functions. One is to localize to DNA breaks, recruiting the DNA repair machinery, which includes the ALS-linked protein FUS (Mar 2018 news, Naumann et al., 2018). Cancer cells often already have DNA repair defects, making them especially sensitive to PARP inhibition. Blocking PARP1, and sometimes PARP2, can selectively kill cancer cells because they run out of options to fix their genomes.

Overactivation of PARPs, however can incite inflammation, and may even contribute to neurodegenerative disease. Thus, scientists are increasingly repurposing PARP inhibitors as potential medicines for a variety of conditions, including stroke, traumatic brain injury and cardiovascular disease (Berger et al., 2017).

Two Pathways for TDP-43 Aggregation

Bonini and colleagues first discovered a potential link between PARPs and ALS studying how TDP-43 mediates neurotoxicity. In ALS, this normally nuclear protein accumulates and aggregates in the cytoplasm of neurons. Their approach: identify genes that, when downregulated, would mitigate the toxicity of TDP-43 in the fly eye (McGurk et al., 2018).

“One of the most potent modifiers from that screen was the knockdown of this PAR polymerase or PARP, tankyrase,” said Shorter. “It really gave almost a complete rescue.” Tankyrase is also known as PARP5; it promotes cell cycle progression, telomere elongation and exocytosis, and has also been considered as a cancer drug target.

Tankyrase downregulation also restored the normal lifespan of neuronal fruit fly model of ALS. It promoted nuclear localization of TDP-43 in neurons while diminishing cytoplasmic accumulation.

How could PARP downregulation reduce this neurotoxicity? It’s possible TDP-43 is PARylated, though the researchers saw no evidence of this in culture. What they did see is that TDP-43 binds PAR within its nuclear localization sequence. In addition, TDP-43 co-localized with this sugar in stress granules, membrane-less organelles that store proteins and RNAs to ensure only essential proteins are synthesized under stressful conditions.

All roads that lead to TDP-43 inclusions. In ALS, TDP-43 could aggregate in neurons by multiple mechanisms [Courtesy of Boeynaems and Gitler, 2018, Molecular Cell].

Short-term stress granules could act as a sort of “safe harbor,” preventing the TDP-43 from forming more toxic aggregates, wrote Aaron Gitler and Steven Boeynaems, of Stanford University School of Medicine in California, in a Molecular Cell commentary accompanying the study (Boeynaems and Gitler, 2018). But long-term stress — as in a neuron of a person with ALS — could force TDP into a permanently aggregated, and potentially more dangerous, conformation contributing to the disease.

Normally, stress granules disassemble when no longer needed. But under conditions of prolonged stress, akin to that in ALS, TDP-43 localized to inclusions distinct from stress granules in cultured cells. It also became phosphorylated, a sign it had turned toxic.

The researchers also noted that fragments of TDP-43 that lacked PAR-binding sequences did not accumulate in stress granules under stressful conditions. Instead, they localized to other inclusions.

The results suggest “there are two separate pathways: that you could go the stress granule route, or you could go a fibrillar pathology route,” commented Ben Wolozin of Boston University School of Medicine, who was not involved in the research. “That needs to be investigated more, but I think that could be important.” He speculated that during ALS, some signal—perhaps phosphorylation—shunts TDP-43 away from stress granules and into other aggregates which contribute to neurotoxicity.

In a subsequent study, the researchers found further reason to suspect PARP activity goes awry in ALS (McGurk et al., 2018). People who had ALS had elevated levels of nuclear PAR in their spinal cord motor neurons. That suggests abnormally high PARP activity in those cells.

Alternatively, the high PAR could also be explained by the presence of DNA damage, noted Ted Dawson, a neurologist at the Johns Hopkins University School of Medicine in Baltimore who was not involved in the studies. Other studies have also observed signs of DNA damage and inefficient repair in ALS models and human brain tissue (Aguirre et al., 2005; Kisby et al., 1997).

Repurposing PARP inhibitors?

Could overactivation of PARPs contribute to ALS? The results in fruit fly models of ALS suggest this is a possibility. But if PAR helps promote the recruitment of TDP-43 to stress granules, how does reducing levels of PAR mitigate its toxicity?

TDP-43 aggregates, a toxic sludge? The cytoplasmic buildup of TDP-43 may contribute to ALS by multiple mechanisms. This may include a power drop in neurons due to the inability to replenish mature oligodendroglial populations (see Wang et al., 2018). [Courtesy of Janssens and Broeckhoven, 2013, Human Molecular Genetics. CC BY 4.0.]

Perhaps, Shorter suggested, nuclear import receptors compete with PAR for TDP-43 binding. With less of a PARP around, there might be less PAR, giving the nuclear import system more opportunities to pull TDP-43 back into the nucleus.

To test the idea, they first treated cultures of stressed mammalian cells with three different tankyrase inhibitors. All three diminished the number of TDP-43 aggregates. Then the scientists experimented with cancer drug veliparib, a PARP1/2 inhibitor. In fibroblasts, it too reduced the fraction of cells with TDP-43 aggregates in the cytoplasm.

The results suggest that blocking key PARPs might be beneficial for most cases of ALS, in which TDP-43 aggregates and likely contributes to motor neuron toxicity. This idea joins several other possible ways to manage these inclusions in ALS. To name a few: Shorter and colleagues are zeroing in on nuclear import receptors that can disaggregate TDP-43 (April 2018 news; Guo et al., 2018). Todd Cohen at the University of North Carolina in Chapel Hill is taking aim at an “acetylation switch” in TDP-43 to identify small molecules that can dissolve TDP-43 aggregates, too (September 2017 news, Wang et al., 2017). And, researchers in Japan are developing antibodies that specifically target and destroy these potentially toxic inclusions (July 2018 news; Tamaki et al., 2018).

The big advantage of PARP inhibitors is that a few are already approved for clinical use. “There are a lot of really great compounds out there,” said Shorter. The FDA has approved three PARP1/2 inhibitors for ovarian cancer: olaparib (Astrazeneca), rucaparib (Clovis Oncology), and niraparib (Tesaro). Olaparib and talazoparib (Pfizer) are also used for breast cancer. Rucaparib also inhibits PARP5, as does olaparib at high doses (Haikarainen et al., 2014; Narwal et al., 2012).

Most cancer patients using these medicines tolerate them well in comparison to chemotherapy, at least short-term; there hasn’t been time to collect long-term data (for review, see Mirza et al., 2018). Using pre-approved drugs could speed development of an ALS treatment, Shorter said.

Many questions remain. For one, Shorter said, it is not clear whether PARP inhibitors break up existing TDP-43 aggregates in neurons, in addition to preventing new ones from forming. That’s important because neurons in people diagnosed with ALS may already have TDP-43 pathology.

Engage. Make It So. There are currently 5 PARP inhibitors available for clinical use to manage certain types of advanced-stage cancer in the US. Imaging tracers are now being developed to facilitate the clinical testing of these drugs for other indications by enabling measurement of target engagement [Courtesy of Carney et al., 2018, Nature Communications. CC BY 4.0].

Dawson noted that it will also be important to determine whether this strategy is of benefit in vertebrate models of the disease.

Moreover, the jury is still out whether this strategy could only be of benefit to TDP-43-positive forms of the disease. For example, some scientists have suggested that it would be beneficial to boost, not inhibit, PARP activity, in FUS ALS. The idea is to give these enzymes extra time to repair DNA breaks in ALS neurons (Mar 2018 news). Indeed, PARP 1/2 inhibitor veliparib treatment can cause FUS to mislocalize and aggregate in the cytosol of cultured cells, further contributing to cytotoxicity (Naumann et al., 2018).

Meanwhile, neurologists including Dawson worry about the long-term use of these drugs in treating chronic neurodegenerative diseases such as ALS.

“If you’re going to be using PARP inhibitors in humans, you’re going to be interfering with the DNA repair process,” he cautioned. “In these chronic diseases, that’ll be one of the things that will need to be taken under consideration.” However, he remains open to this treatment strategy for certain conditions with limited therapeutic options. Dawson and colleagues, in fact, are investigating their use as a potential treatment for Parkinson’s disease (Kam et al., 2018).

“I think in ALS, you’d want to have tankyrase inhibitors — [inhibitors] for PARP5 instead of PARP1/2,” Dawson suggested. These enzymes probably wouldn’t be involved in the DNA repair process, he said, making them potentially a safer option. Several highly selective PARP5 inhibitors are being developed for cancer (Haikarainen et al., 2014), though none have been clinically tested.

“[PARP inhibitors] could be interesting therapeutic options for ALS/FTD,” concluded Gitler and Boeynaems. “They potentially prevent cytoplasmic aggregation and additionally promote nuclear import—preventing, in one fell swoop, the two key steps on the path to pathological TDP-43 aggregation.”

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Filter articles published since 2015 by topic, disease, or article type.

Guidlines for filtering

Results are filtered to show all matching articles from a particular category, and to show only articles that match all selected categories.

For instance, if "Biomarkers" and "Genetics" are selected in the Topic category, and "Multiple sclerosis" is selected in the Disease category, all results that match EITHER the Biomarkers OR Genetics Topic category will be shown, but only if they also match the Multiple sclerosis Disease category; i.e. Boolean search of [("Biomarkers" OR "Genetics") AND "multiple sclerosis"]